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BACKGROUND: Pulmonary hypertension (PH) complicating idiopathic pulmonary fibrosis (IPF) is associated to worse outcome. There is a great need for a non-invasive diagnostic modality to detect and evaluate the severity of pulmonary vascular disease (PVD). 99mTc-PulmoBind is a novel imaging agent that binds to the adrenomedullin (AM) receptor on the pulmonary microvascular endothelium. SPECT imaging employing the endothelial cell tracer 99mTc-PulmoBind was used to assess PVD associated with lung fibrosis. METHODS: Rats with selective right lung bleomycin-induced fibrosis were compared to control rats. SPECT imaging was performed after three weeks with 99mTc-PulmoBind and 99mTc-macroaggregates of albumin (MAA). PH and right ventricular (RV) function were assessed by echocardiography. Lung perfusion was evaluated by fluorescent microangiography. Lung AM receptor expression was measured by qPCR and by immunohistology. Relevance to human IPF was explored by measuring AM receptor expression in lung biopsies from IPF patients and healthy controls. RESULTS: The bleomycin group developed preferential right lung fibrosis with remodeling and reduced perfusion as assessed with fluorescent microangiography. These rats developed PH with RV hypertrophy and dysfunction. 99mTc-PulmoBind uptake was selectively reduced by 50% in the right lung and associated with reduced AM receptor expression, PH and RV hypertrophy. AM receptor was co-expressed with the endothelial cell protein CD31 in alveolar capillaries, and markedly reduced after bleomycin. Quantitative dynamic analysis of 99mTc-PulmoBind uptake in comparison to 99mTc-MAA revealed that the latter distributed only according to flow, with about 60% increased left lung uptake while left lung uptake of 99mTc-PulmoBind was not affected. Lung from human IPF patients showed important reduction in AM receptor expression closely associated with CD31. CONCLUSIONS: SPECT imaging with 99mTc-PulmoBind detects PVD and its severity in bleomycin-induced lung fibrosis. Reduced AM receptor expression in human IPF supports further clinical development of this imaging approach.
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Adrenomedulina/análogos & derivados , Bleomicina/toxicidad , Endotelio Vascular/metabolismo , Hipertensión Pulmonar/metabolismo , Fragmentos de Péptidos/metabolismo , Fibrosis Pulmonar/metabolismo , Tomografía Computarizada de Emisión de Fotón Único/métodos , Adrenomedulina/metabolismo , Animales , Antibióticos Antineoplásicos/toxicidad , Endotelio Vascular/diagnóstico por imagen , Endotelio Vascular/efectos de los fármacos , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/diagnóstico por imagen , Masculino , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/diagnóstico por imagen , Radiofármacos/metabolismo , Ratas , Ratas WistarRESUMEN
Importance: Continuous glucose monitoring (CGM) has been shown to be beneficial for adults with type 2 diabetes using intensive insulin therapy, but its use in type 2 diabetes treated with basal insulin without prandial insulin has not been well studied. Objective: To determine the effectiveness of CGM in adults with type 2 diabetes treated with basal insulin without prandial insulin in primary care practices. Design, Setting, and Participants: This randomized clinical trial was conducted at 15 centers in the US (enrollment from July 30, 2018, to October 30, 2019; follow-up completed July 7, 2020) and included adults with type 2 diabetes receiving their diabetes care from a primary care clinician and treated with 1 or 2 daily injections of long- or intermediate-acting basal insulin without prandial insulin, with or without noninsulin glucose-lowering medications. Interventions: Random assignment 2:1 to CGM (n = 116) or traditional blood glucose meter (BGM) monitoring (n = 59). Main Outcomes and Measures: The primary outcome was hemoglobin A1c (HbA1c) level at 8 months. Key secondary outcomes were CGM-measured time in target glucose range of 70 to 180 mg/dL, time with glucose level at greater than 250 mg/dL, and mean glucose level at 8 months. Results: Among 175 randomized participants (mean [SD] age, 57 [9] years; 88 women [50%]; 92 racial/ethnic minority individuals [53%]; mean [SD] baseline HbA1c level, 9.1% [0.9%]), 165 (94%) completed the trial. Mean HbA1c level decreased from 9.1% at baseline to 8.0% at 8 months in the CGM group and from 9.0% to 8.4% in the BGM group (adjusted difference, -0.4% [95% CI, -0.8% to -0.1%]; P = .02). In the CGM group, compared with the BGM group, the mean percentage of CGM-measured time in the target glucose range of 70 to 180 mg/dL was 59% vs 43% (adjusted difference, 15% [95% CI, 8% to 23%]; P < .001), the mean percentage of time at greater than 250 mg/dL was 11% vs 27% (adjusted difference, -16% [95% CI, -21% to -11%]; P < .001), and the means of the mean glucose values were 179 mg/dL vs 206 mg/dL (adjusted difference, -26 mg/dL [95% CI, -41 to -12]; P < .001). Severe hypoglycemic events occurred in 1 participant (1%) in the CGM group and in 1 (2%) in the BGM group. Conclusions and Relevance: Among adults with poorly controlled type 2 diabetes treated with basal insulin without prandial insulin, continuous glucose monitoring, as compared with blood glucose meter monitoring, resulted in significantly lower HbA1c levels at 8 months. Trial Registration: ClinicalTrials.gov Identifier: NCT03566693.
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Glucemia/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Control Glucémico/métodos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Anciano , Intervalos de Confianza , Diabetes Mellitus Tipo 2/sangre , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Periodo Posprandial , Tamaño de la Muestra , Factores de Tiempo , Resultado del TratamientoRESUMEN
Numerous clinical conditions can lead to organ fibrosis and functional failure. There is a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. GPR40 and GPR84 are G protein-coupled receptors with free fatty acid ligands and are associated with metabolic and inflammatory disorders. Although GPR40 and GPR84 are involved in diverse physiological processes, no evidence has demonstrated the relevance of GPR40 and GPR84 in fibrosis pathways. Using PBI-4050 (3-pentylbenzeneacetic acid sodium salt), a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward GPR40 and GPR84, respectively, we uncovered an antifibrotic pathway involving these receptors. In experiments using Gpr40- and Gpr84-knockout mice in models of kidney fibrosis (unilateral ureteral obstruction, long-term post-acute ischemic injury, and adenine-induced chronic kidney disease), we found that GPR40 is protective and GPR84 is deleterious in these diseases. Moreover, through binding to GPR40 and GPR84, PBI-4050 significantly attenuated fibrosis in many injury contexts, as evidenced by the antifibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models. Therefore, GPR40 and GPR84 may represent promising molecular targets in fibrosis pathways. We conclude that PBI-4050 is a first-in-class compound that may be effective for managing inflammatory and fibrosis-related diseases.
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Enfermedades Renales/patología , Receptores Acoplados a Proteínas G/metabolismo , Insuficiencia Renal Crónica/patología , Animales , Fibrosis/genética , Fibrosis/metabolismo , Fibrosis/patología , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Ratones , Ratones Noqueados , Receptores Acoplados a Proteínas G/genética , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismoRESUMEN
Genome-wide association studies have found >60 loci that confer genetic susceptibility to type 1 diabetes (T1D). Many of these are defined only by anonymous single nucleotide polymorphisms: the underlying causative genes, as well as the molecular bases by which they mediate susceptibility, are not known. Identification of how these variants affect the complex mechanisms contributing to the loss of tolerance is a challenge. In this study, we performed systematic analyses to characterize these variants. First, all known genes in strong linkage disequilibrium (r(2) > 0.8) with the reported single nucleotide polymorphisms for each locus were tested for commonly occurring nonsynonymous variations. We found only a total of 22 candidate genes at 16 T1D loci with common nonsynonymous alleles. Next, we performed functional studies to examine the effect of non-HLA T1D risk alleles on regulating expression levels of genes in four different cell types: EBV-transformed B cell lines (resting and 6 h PMA stimulated) and purified CD4(+) and CD8(+) T cells. We mapped cis-acting expression quantitative trait loci and found 24 non-HLA loci that affected the expression of 31 transcripts significantly in at least one cell type. Additionally, we observed 25 loci that affected 38 transcripts in trans. In summary, our systems genetics analyses defined the effect of T1D risk alleles on levels of gene expression and provide novel insights into the complex genetics of T1D, suggesting that most of the T1D risk alleles mediate their effect by influencing expression of multiple nearby genes.
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Diabetes Mellitus Tipo 1/genética , Predisposición Genética a la Enfermedad , Variación Genética , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Línea Celular Transformada , Epistasis Genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Estudios de Asociación Genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Leucocitos Mononucleares/metabolismo , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Reproducibilidad de los ResultadosRESUMEN
PURPOSE: The adrenomedullin receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an adrenomedullin receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study. METHODS: Thirty patients with pulmonary arterial hypertension (PAH, n = 23) or chronic thromboembolic PH (CTEPH, n = 7) in WHO functional class II (n = 26) or III (n = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi 99mTc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month. RESULTS: PulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with â¼50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution. CONCLUSIONS: In this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using 99mTc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and direct comparisons to lung perfusion agents such as labeled macro-aggregates of albumin are needed. CLINICAL TRIAL: ClinicalTrials.gov, NCT02216279.
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Endotelio Vascular/diagnóstico por imagen , Hipertensión Pulmonar/diagnóstico por imagen , Pulmón/irrigación sanguínea , Imagen Molecular/efectos adversos , Seguridad , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Hipertensión Pulmonar/patología , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
This phase I study (NCT01539889) evaluated the safety, efficacy, and dosing of PulmoBind for molecular imaging of pulmonary circulation. PulmoBind is a ligand of the adrenomedullin receptor abundantly distributed in lung capillaries. Labeled with 99mTc, it allows single-photon emission computed tomographic (SPECT) imaging of lung perfusion. In preclinical studies, PulmoBind scans enabled detection of lung perfusion defects and quantification of microcirculatory occlusion caused by pulmonary hypertension. Healthy humans ( N = 20) were included into escalating groups of 5 mCi ( n = 5), 10 mCi ( n = 5), or 15 mCi ( n = 10) 99mTc-PulmoBind. SPECT imaging was serially performed, and 99mTc-PulmoBind dosimetric analysis was accomplished. The radiochemical purity of 99mTc-PulmoBind was greater than 95%. There were no safety concerns at the three dosages studied. Imaging revealed predominant and prolonged lung uptake with a mean peak extraction of 58% ± 7%. PulmoBind was well tolerated, with no clinically significant adverse event related to the study drug. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent imaging. The postural lung perfusion gradient was detectable. 99mTc-PulmoBind is safe and provides good quality lung perfusion imaging. The safety/efficacy of this agent can be tested in disorders of pulmonary circulation such as pulmonary arterial hypertension.
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This phase I study (NCT01539889) evaluated the safety, efficacy, and dosing of PulmoBind for molecular imaging of pulmonary circulation. PulmoBind is a ligand of the adrenomedullin receptor abundantly distributed in lung capillaries. Labeled with 99mTc, it allows single-photon emission computed tomographic (SPECT) imaging of lung perfusion. In preclinical studies, PulmoBind scans enabled detection of lung perfusion defects and quantification of microcirculatory occlusion caused by pulmonary hypertension. Healthy humans (N â=â 20) were included into escalating groups of 5 mCi (n â=â 5), 10 mCi (n â=â 5), or 15 mCi (n â=â 10) 99mTc-PulmoBind. SPECT imaging was serially performed, and 99mTc-PulmoBind dosimetric analysis was accomplished. The radiochemical purity of 99mTc-PulmoBind was greater than 95%. There were no safety concerns at the three dosages studied. Imaging revealed predominant and prolonged lung uptake with a mean peak extraction of 58% ± 7%. PulmoBind was well tolerated, with no clinically significant adverse event related to the study drug. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent imaging. The postural lung perfusion gradient was detectable. 99mTc-PulmoBind is safe and provides good quality lung perfusion imaging. The safety/efficacy of this agent can be tested in disorders of pulmonary circulation such as pulmonary arterial hypertension.
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Endotelio Vascular/patología , Pulmón/patología , Imagen Molecular , Receptores de Adrenomedulina/metabolismo , Adrenomedulina/análogos & derivados , Adrenomedulina/química , Adrenomedulina/metabolismo , Adulto , Anciano , Diástole , Femenino , Humanos , Concentración de Iones de Hidrógeno , Ligandos , Masculino , Microcirculación , Persona de Mediana Edad , Fragmentos de Péptidos/química , Radiometría , Sístole , Tecnecio/química , Adulto JovenRESUMEN
BACKGROUND: This study aims to assess the long-term outcomes of a modified pneumatic reduction protocol for intussusception at the Vietnam National Hospital of Pediatrics, an institution with a significant patient load in a lower-middle-income country. PATIENTS AND METHODS: A single center, retrospective cohort observational study was conducted to examine patients who underwent modified fluoroscopic-guided air-enema reduction (FGAR) for intussusception from January 2016 to December 2017. Data on patient demographics, complication rates, and the incidence of long-term recurrence was collected. RESULTS: Between January 2016 and December 2017, a total of 3562 patients underwent modified FGAR at our institution, including 2313 males (64.9%) and 1249 females (35.1%). The median age was 19 months (range: 1-170), and the median FGAR procedure duration was 4 min (range: 2-24). The median hospital stay was 1 day (range: 1-31). Successful reduction was achieved in 98.7% of cases, with 43 unsuccessful cases and 4 cases of perforated bowel requiring surgery. Twenty patients, presenting with severe symptoms due to delayed treatment seeking, were admitted to the pediatric intensive care unit (ICU) post-FGAR. No mortality or severe morbidity was reported. Over a median 6-year follow-up, intussusception recurred in 198 patients, accounting for 5.6% of the cohort, with 97% of recurrences occurring within the first year post-reduction. Infants and children under 12 months of age had the highest complication rates, including failed FGAR, complicated intussusception, ICU admission, or recurrence, compared to other age groups, and this difference was statistically significant (p < 0.05). CONCLUSION: The modified FGAR protocol has been demonstrated to be safe and feasible, with a very high success rate, low complication rate, and low recurrence rate. Although further comparative studies are needed to confirm its reproducibility, it should be considered a promising approach for children in low-to middle-income countries. LEVEL OF EVIDENCE: Level III.
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OBJECTIVE: To compare postprandial glucose excursions following a bolus with inhaled technosphere insulin (TI) or subcutaneous rapid-acting analog (RAA) insulin. RESEARCH DESIGN AND METHODS: A meal challenge was completed by 122 adults with type 1 diabetes who were using multiple daily injections (MDI), a nonautomated pump, or automated insulin delivery (AID) and who were randomized to bolus with their usual RAA insulin (n = 61) or TI (n = 61). RESULTS: The primary outcome, the treatment group difference in area under the curve for glucose >180 mg/dL over 2 h, was less with TI versus RAA (adjusted difference -12 mg/dL, 95% CI -22 to -2, P = 0.02). With TI, the glucose excursion was smaller (P = 0.01), peak glucose lower (P = 0.01), and time to peak glucose shorter (P = 0.006). Blood glucose <70 mg/dL occurred in one participant in each group. CONCLUSIONS: Postmeal glucose excursion was smaller with TI than with RAA insulin in a cohort that included both AID and MDI users.
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CONTEXT: Early inflammatory thyroid eye disease (TED) can lead to symptomatic chronic disease, including disabling proptosis. Teprotumumab, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor, previously demonstrated efficacy in acute, high-inflammation TED trials. OBJECTIVE: We present data from the first placebo-controlled trial with teprotumumab in chronic/low disease activity TED. METHODS: This randomized double-masked, placebo-controlled trial, conducted at 11 US centers, enrolled adult participants with TED duration of 2 to 10 years, Clinical Activity Score (CAS) ≤ 1 or no additional inflammation or progression in proptosis/diplopia for ≥1 year, proptosis ≥3 mm from before TED and/or from normal, euthyroid/mildly hypo/hyperthyroid, no prior teprotumumab, and no steroids within 3 weeks of baseline. Patients received (2:1) intravenous teprotumumab or placebo once every 3 weeks (total 8 infusions). The primary endpoint was proptosis (mm) improvement at Week 24. Adverse events (AEs) were assessed. RESULTS: A total of 62 (42 teprotumumab and 20 placebo) patients were randomized. At Week 24, least squares mean (SE) proptosis improvement was greater with teprotumumab (-2.41 [0.228]) than with placebo (-0.92 [0.323]), difference -1.48 (95% CI -2.28, -0.69; P = .0004). Proportions of patients with AEs were similar between groups. Hyperglycemia was reported in 6 (15%) vs 2 (10%) and hearing impairment in 9 (22%) vs 2 (10%) with teprotumumab and placebo, respectively. AEs led to discontinuation in 1 teprotumumab (left ear conductive hearing loss with congenital anomaly) and 1 placebo patient (infusion-related). There were no deaths. CONCLUSION: Teprotumumab significantly improved proptosis vs placebo in longstanding/low inflammation TED, demonstrating efficacy regardless of disease duration/activity. The safety profile was comparable to that previously reported.
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Exoftalmia , Oftalmopatía de Graves , Adulto , Humanos , Anticuerpos Monoclonales Humanizados/efectos adversos , Oftalmopatía de Graves/tratamiento farmacológico , Inflamación , Inhibidores de Proteínas Quinasas , Método Doble CiegoRESUMEN
BACKGROUND: Delays in diagnosis and treatment from first noticeable breast cancer symptoms are associated with poor outcomes. Understanding the reasons and barriers for patients' delay in seeking medical care is critical to mitigating the problem. METHODS: In-person surveys were conducted among 462 women, aged 18-79, with incident breast cancer cases, recruited from two cancer hospitals in North Vietnam. Delay, defined as the time interval between symptom recognition to the diagnosis and initiation of treatment equal to or exceeding 3 months, was categorized as follows: no delay (<3 months), moderate delay (3-8 months), and serious delay (≥9 months). Multivariable multinomial logistic regression was applied in data analyses. RESULTS: Over one-quarter patients (31.5%) experienced moderate delays, and close to one-fifth (17.5%) experienced serious delays. Adjusted odds ratios and 95% confidence intervals for moderate and serious delays were 5.60 (3.00-10.47) and 4.25 (2.05-8.85) for financial and physical barriers, respectively. Moderate delay was positively associated with psychological barriers (5.55 [1.75-17.57]) and lack of proper knowledge (3.15 [1.47-6.74]). The associations of barriers with delays in diagnosis and treatment appeared stronger among women living in rural areas. A lack of proper knowledge was significantly associated with delay among young women (<45 years old) and those with high incomes, while psychological barriers were significantly associated with delay among older women (≥45 years old). CONCLUSION: Delays in diagnosis and treatment are common among Vietnamese breast cancer patients and are affected by several noted barriers. Proper policy needs to be developed to address this public health issue.
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Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Diagnóstico Tardío/psicología , Conocimientos, Actitudes y Práctica en Salud , Aceptación de la Atención de Salud , Tiempo de Tratamiento , Adolescente , Adulto , Factores de Edad , Anciano , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/psicología , Detección Precoz del Cáncer , Femenino , Accesibilidad a los Servicios de Salud , Humanos , Incidencia , Persona de Mediana Edad , Población Rural , Factores Socioeconómicos , Vietnam/epidemiología , Adulto JovenRESUMEN
OBJECTIVE: To explore the effect of discontinuing continuous glucose monitoring (CGM) after 8 months of CGM use in adults with type 2 diabetes treated with basal without bolus insulin. RESEARCH DESIGN AND METHODS: This multicenter trial had an initial randomization to either real-time CGM or blood glucose monitoring (BGM) for 8 months followed by 6 months in which the BGM group continued to use BGM (n = 57) and the CGM group was randomly reassigned either to continue CGM (n = 53) or discontinue CGM with resumption of BGM for glucose monitoring (n = 53). RESULTS: In the group that discontinued CGM, mean time in range (TIR) 70-180 mg/dL, which improved from 38% before initiating CGM to 62% after 8 months of CGM, decreased after discontinuing CGM to 50% at 14 months (mean change from 8 to 14 months -12% [95% CI -21% to -3%], P = 0.01). In the group that continued CGM use, little change was found in TIR from 8 to 14 months (baseline 44%, 8 months 56%, 14 months 57%, mean change from 8 to 14 months 1% [95% CI -11% to 12%], P = 0.89). Comparing the two groups at 14 months, the adjusted treatment group difference in mean TIR was -6% (95% CI -16% to 4%, P = 0.20). CONCLUSIONS: In adults with type 2 diabetes treated with basal insulin who had been using real-time CGM for 8 months, discontinuing CGM resulted in a loss of about one-half of the initial gain in TIR that had been achieved during CGM use.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Adulto , Glucemia , Automonitorización de la Glucosa Sanguínea/métodos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéuticoRESUMEN
The acute respiratory distress syndrome (ARDS) is characterized by intense dysregulated inflammation leading to acute lung injury (ALI) and respiratory failure. There are no effective pharmacologic therapies for ARDS. Colchicine is a low-cost, widely available drug, effective in the treatment of inflammatory conditions. We studied the effects of colchicine pre-treatment on oleic acid-induced ARDS in rats. Rats were treated with colchicine (1 mg/kg) or placebo for three days prior to intravenous oleic acid-induced ALI (150 mg/kg). Four hours later they were studied and compared to a sham group. Colchicine reduced the area of histological lung injury by 61%, reduced lung edema, and markedly improved oxygenation by increasing PaO2/FiO2 from 66 ± 13 mmHg (mean ± SEM) to 246 ± 45 mmHg compared to 380 ± 18 mmHg in sham animals. Colchicine also reduced PaCO2 and respiratory acidosis. Lung neutrophil recruitment, assessed by myeloperoxidase immunostaining, was greatly increased after injury from 1.16 ± 0.19% to 8.86 ± 0.66% and significantly reduced by colchicine to 5.95 ± 1.13%. Increased lung NETosis was also reduced by therapy. Circulating leukocytosis after ALI was not reduced by colchicine therapy, but neutrophils reactivity and CD4 and CD8 cell surface expression on lymphocyte populations were restored. Colchicine reduces ALI and respiratory failure in experimental ARDS in relation with reduced lung neutrophil recruitment and reduced circulating leukocyte activation. This study supports the clinical development of colchicine for the prevention of ARDS in conditions causing ALI.
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Lesión Pulmonar Aguda/tratamiento farmacológico , Colchicina/farmacología , Pulmón/efectos de los fármacos , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Lesión Pulmonar Aguda/sangre , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patología , Animales , Modelos Animales de Enfermedad , Humanos , Pulmón/patología , Infiltración Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Ácido Oléico/toxicidad , Ratas , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/patologíaRESUMEN
AIMS: Heart failure with reduced ejection fraction (HFrEF) causes lung remodelling with myofibroblasts proliferation and fibrosis leading to a restrictive lung syndrome with pulmonary hypertension (PH) and right ventricular (RV) dysfunction. PBI-4050 is a first-in-class anti-fibrotic, anti-inflammatory, and anti-proliferative compound. The present study evaluated the therapeutic impact of PBI-4050 on PH in an HFrEF model. METHODS AND RESULTS: HFrEF was induced after myocardial infarction (MI) in rats. Two weeks later, sham-operated and MI groups received PBI-4050 (200 mg/kg/day by gavage) or saline for 3 weeks. Animals were analysed according to infarct size as large (≥30% left ventricle) or medium MI (<30%). Large MI caused PH and RV hypertrophy (RVH) with a restrictive lung syndrome. PBI-4050 did not adversely affect left ventricular (LV) function but markedly reduced PH and RVH and improved RV dysfunction. PBI-4050 reduced lung remodelling and improved respiratory compliance with decreased lung fibrosis, alveolar wall cellular proliferation and α-smooth muscle actin expression. The increased expression of endothelin-1 (ET-1), transforming growth factor beta (TGF-ß), interleukin-6 (IL-6) and of tissue inhibitor of metalloprotease-1 in the lungs from HFrEF were reduced with PBI-4050 therapy. Activation of isolated human lung fibroblasts (HLFs) to a myofibroblastic pro-fibrogenic phenotype was markedly reduced by PBI-4050. The fatty acid receptor GPR84 was increased in HFrEF lungs and in activated HLFs, and reduced by PBI-4050. GPR84 agonists activated fibrogenesis in HLFs and finally, PBI-4050 reduced ERK1/2 phosphorylation. CONCLUSIONS: PBI-4050 reduces PH and RVH in HFrEF by decreasing lung fibrosis and remodelling. This novel agent decreases the associated restrictive lung syndrome and recovers RV function. A contributing mechanism involves reducing the activation of lung fibroblasts by IL-6, TGF-ß, and ET-1 by antagonism of GPR84 and reduced ERK1/2 phosphorylation. PBI-4050 is a novel promising therapy for targeting lung remodelling in group II PH.
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Acetatos/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Ventrículos Cardíacos/efectos de los fármacos , Hipertensión Pulmonar/prevención & control , Hipertrofia Ventricular Derecha/prevención & control , Pulmón/efectos de los fármacos , Fibrosis Pulmonar/prevención & control , Disfunción Ventricular Derecha/prevención & control , Función Ventricular Derecha/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Endotelina-1/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/fisiopatología , Interleucina-6/metabolismo , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Masculino , Fosforilación , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/fisiopatología , Ratas Wistar , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
BACKGROUND: Brain metastases are challenging daily practice in oncology and remain a compartmental problem since most anti-cancer drugs do not cross the blood-brain barrier at relevant pharmacological concentrations. METHODS: In a young woman with HER2-overexpressing breast cancer resistant to standard treatments, at the time of brain metastases progression, a ventricular reservoir was implanted for intrathecal drug injections and detailed pharmacokinetic studies. RESULTS: A first association of intrathecal trastuzumab with intravenous cisplatin was offered to the patient. For trastuzumab, the mean cerebrospinal fluid trough concentration of 53.4 mg/L reached relevant levels, enabling the stabilization of the metastases. Adding intravenous cisplatin was not beneficial, since the cerebrospinal fluid exposure was almost undetectable under 0.08 mg/L. We then offered the patient an intrathecal combination of trastuzumab and methotrexate, because of their in vitro synergic cytotoxicity. The cerebrospinal fluid peak of methotrexate was 1037 µmol/L at 2 h, and the concentrations remained above the theoretical therapeutic concentration. After 2 months of this drug combination, we obtained an excellent response on the brain metastases. CONCLUSION: Our preliminary study supports the interest of a compartmental approach through a direct administration of drugs into the cerebrospinal fluid for the treatment of breast cancer brain metastases.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Encefálicas/terapia , Neoplasias de la Mama/patología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/tratamiento farmacológico , Cisplatino/administración & dosificación , Cisplatino/farmacocinética , Femenino , Humanos , Infusiones Intravenosas , Inyecciones Espinales , Imagen por Resonancia Magnética , Receptor ErbB-2/metabolismo , Trastuzumab/administración & dosificación , Trastuzumab/farmacocinética , Resultado del TratamientoRESUMEN
INTRODUCTION: Adrenomedullin receptors are highly expressed in human alveolar capillaries and provide a molecular target for imaging the integrity of pulmonary microcirculation. In this work, we aimed to develop a NOTA-derivatized adrenomedullin analog (DFH17), radiolabeled with [18F]AlF, for PET imaging of pulmonary microcirculation. METHODS: Highly concentrated [18F](AlF)2+ (15⯵L) was produced from purified fluorine-18 in NaCl 0.9%. Various complexation experiments were carried out at Al-to-NOTA molar ratios ranging from 1:1 to 1:40 to assess optimal radiolabeling conditions before using the peptide. DFH17 peptide (2â¯mM, pHâ¯4) was radiolabeled with [18F](AlF)2+ for 15â¯min at 100⯰C in a total volume of 60⯵L. As part of the radiolabeling process, parameters such as fluorine-18 activity (~37 and 1480â¯MBq), concentration of AlCl3 (0.75, 2, 3, 6 or 10â¯mM) and the effects of hydrophilic organic solvent (aqueous vs ethanol 50%) were studied. The final formulation was tested for purity, identity and stability in saline. Initial in vivo evaluation of [18F]AlF-DFH17 was performed in normal rats by PET/CT. RESULTS: The scaled-up production of [18F]AlF-DFH17 was performed in high radiochemical and chemical purities in an overall radiochemical yield of 22-38% (at end-of-synthesis) within 60â¯min. The final formulation was stable in saline at different radioactive concentrations for 8â¯h. PET evaluation in rats revealed high lung-to-background ratios and no defluorination in vivo up to 1â¯h post-injection. CONCLUSION: The novel radioconjugate [18F]AlF-DFH17 appears to be a promising PET ligand for pulmonary microcirculation imaging.
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Adrenomedulina/química , Radioisótopos de Flúor/química , Compuestos Heterocíclicos/química , Tomografía de Emisión de Positrones/métodos , Circulación Pulmonar , Adrenomedulina/farmacocinética , Estabilidad de Medicamentos , Radioisótopos de Flúor/farmacocinética , Compuestos Heterocíclicos con 1 Anillo , Marcaje Isotópico , Distribución TisularRESUMEN
AIMS: This paper describes a simple technique of axillary and breast massage which improves the successful identification of blue sentinel nodes using patent blue dye alone. METHODS: Patent blue dye was injected in the subdermal part of the retroaroelar area in 167 patients having surgical treatment for invasive breast cancer. Three stage axillary lymphatic massage was performed prior to making the axillary incision for sentinel lymph node biopsy. All patients had completion axillary sampling or clearance. RESULTS: A blue lymphatic duct leading to lymph nodes of the first drainage was identified in 163 (97%) of the patients. Results are compared with 168 patients who had sentinel lymph node biopsy using blue dye without axillary massage. Allergic reactions were observed in four patients (1.2%). CONCLUSION: Three stage axillary lymphatic massage improves the successful identification of a blue sentinel lymph node in breast cancer patients.
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Acute coronary syndrome (ACS) is characterized by unstable plaque with thrombotic process involving central role of platelets. The diagnosis and prediction of significant coronary artery disease (CAD) in non-ST-elevation ACS (NSTE-ACS) can be challenging. The central role of platelets in acute atherothrombosis in NSTE-ACS spurred appreciable interest in the diagnostic and predictive role of platelet activity. Mean platelet volume (MPV) is one of the most promising laboratory markers in patients with CAD. This retrospective study was designed to investigate the diagnostic and predictive value of high MPV levels in patients with NSTE-ACS with significant CAD. A total of 213 patients (men 53%, mean age 61 ± 12.3 years) with NSTE-ACS were enrolled from 2011 to 2016 from 2 teaching hospitals. Patients' demographic, laboratory, and angiographic data were collected. Significant CAD was defined as ≥70% stenosis in at least 1 major coronary artery. Patients with high MPV (MPV ≥9 fl) had more significant CAD (55% vs 35%, p = 0.005), lower platelet count (204 ± 59 × 1,000/µl vs 246 ± 56 × 1,000/µl, p = 0.001), and higher HbA1c (6.9 vs 6.4, p = 0.02). Patients with significant CAD had higher MPV level (9.2 ± 1.07 vs 8.6 ± 1.03 fl, p = 0.001), higher MPV/platelet ratio (0.46 vs 0.40, p = 0.01), older age (64.5 ± 11 vs 59.2 ± 12 years, p = 0.02), and lower high-density lipoprotein level (42 ± 12 vs 47 ± 16, p = 0.01). Multivariate analysis showed that increased age, high MPV, high troponin, and low high-density lipoprotein levels were associated with significant CAD. Patients with high MPV along with high troponin level demonstrated a 4.8-fold increased risk for significant CAD compared to those with normal MPV and high troponin (odds ratio 4.8, 95% confidence interval 1.31 to 17.6, p = 0.001). In conclusion, considering high MPV in the context of elevated troponin level increases the predictive value of screening for significant CAD, and this result may help determine who is most likely to benefit from cardiac catheterization.
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Síndrome Coronario Agudo/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/diagnóstico , Volúmen Plaquetario Medio , Infarto del Miocardio sin Elevación del ST/sangre , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/mortalidad , Anciano , Enfermedad de la Arteria Coronaria/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio sin Elevación del ST/diagnóstico , Infarto del Miocardio sin Elevación del ST/mortalidad , Valor Predictivo de las Pruebas , Curva ROC , Estudios RetrospectivosRESUMEN
BACKGROUND: It is estimated that 29.1 million people or 9.3% of the US population have diabetes, which contributes to considerable medical and financial burden. Type 2 diabetes mellitus is characterized by insulin resistance and insulin secretion impairment leading to hyperglycemia. The presence of insulin resistance is strongly correlated with obesity. OBJECTIVE: This article reviews the available glucagon-like peptide-1 (GLP-1) receptor agonists and their role in the management of patients with diabetes, to help guide the selection of the most suitable agent for the individualized treatment of patients with type 2 diabetes. DISCUSSION: This article reviews the evidence from phase 3 clinical trials for each of the 5 GLP-1 receptor agonists by comparing them against one another and with other existing therapies, including metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas. Incretin-based therapies have emerged as attractive agents for the treatment of type 2 diabetes. They target the GLP-1 hormone, which is partly responsible for insulin release and for attenuating hyperglycemia during meals (ie, the incretin effect). The 2 classes of incretin-based therapy currently available are GLP-1 receptor agonists and DPP-4 inhibitors, which prevent the breakdown of GLP-1. Both classes are attractive options, given their glucose-lowering effects without the adverse effects of hypoglycemia and weight gain. The different mechanisms of action of these therapies result in generally greater efficacy with GLP-1 receptor agonists, albeit at the expense of slightly increased gastrointestinal symptoms. These agents exert their effects by improving glucose-dependent insulin release, suppressing glucagon release, suppressing hepatic glucose output, and decreasing the rate of gastric emptying, thereby reducing appetite. Currently, 5 GLP-1 receptor agonists are available, including exenatide, liraglutide, albiglutide, dulaglutide, and lixisenatide; semaglutide may soon become available as the newest agent. With the exception of the investigational oral semaglutide, which has shown promising results, the other 5 agents are administered as subcutaneous injections, at different dosing intervals. CONCLUSION: Currently, 5 GLP-1 receptor agonists are available for use in the United States. Although they are all in the same drug class, some significant differences exist among the various GLP-1 receptor agonists. The choice of a specific GLP-1 receptor agonist will depend on the patient preferences, potential adverse effects, and cost.
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BACKGROUND: Pulmonary perfusion is not spatially homogeneously distributed, and its variations could be of diagnostic value in lung vascular disease. PulmoBind is a ligand of the adrenomedullin receptor densely expressed in endothelial cells of lung capillaries. The aim of this study was to evaluate spatial distribution of human lung perfusion by using this novel molecular tracer of the pulmonary vascular endothelium. METHODS: Normal humans (n = 19) enrolled into the PulmoBind phase I trial were studied (Clinicaltrials.gov. NCT01539889 ). They were injected with (99m)Tc-PulmoBind for SPECT imaging. Results were compared with (99m)Tc-PulmoBind in quadruped mammals (dogs, n = 5). Imaging was performed in the supine position and distribution of activity was determined as a function of cumulative voxels along the different anatomical planes. RESULTS: PulmoBind uptake in humans was 58 ± 1 % (mean ± SEM) of the injected dose. Dorsal activity was 18.1 ± 2.1 % greater than ventral, and caudal activity was 25.7 ± 1.6 % greater than cranial. Lateral activity was only mildly higher than medial by 7.0 ± 1.0 %. In supine dogs, similar but higher PulmoBind gradients were present: dorsal 28.6 ± 2.5 %, caudal 34.1 ± 5.0 % and lateral 18.1 ± 2.0 %. CONCLUSIONS: The perfused pulmonary circulation of supine humans, assessed by an adrenomedullin receptor ligand, is not homogeneously distributed with more prominent distribution in dorsal and caudal regions. It is qualitatively similar to a supine quadruped mammal confirming the presence of a microcirculatory gravitational perfusion gradient detectable with this tracer. Future studies are needed to determine if this novel endothelial cell tracer could be used to detect physiologic and pathologic variations of lung perfusion such as in pulmonary hypertension. CLINICAL TRIAL: ClinicalTrial.gov, NCT01539889.